Subjects afflicted with diabetes foot ulcers are a particularly vulnerable population due to an increased incidence of infection and prolonged healing. Innovations that improve wound healing would reduce the number of amputations, decrease costly additional interventions and ultimately increase quality of life. The antibiotic doxycycline is an inhibitor of high levels of active proteases, including metalloproteinases, a proinflammatory molecule in wounds but few studies have examined its effect among diabetic patients with chronic foot ulcers. The purpose of this study is: (1) to determine the effectiveness of topical doxycycline to accelerate the healing of chronic diabetic foot ulcers, (2) describe the molecular changes that occur in diabetic foot ulcers as they heal and (3) detect changes in the patterns of gene expression in healing diabetic wounds treated with topical doxycycline. We hypothesize that diabetic foot ulcers often fail to heal because persistently high levels of pro-inflammatory cytokines present in the wound induce high levels of proteases, which then destroy growth factors, receptors and matrix proteins essential for wound healing. If this hypothesis is correct, then topical treatment of diabetic ulcers with a molecule that reduces inflammation and proteases activity would promote healing by reducing the destruction of endogenous growth factors, receptors, and extracellular matrix proteins that are essential for wound healing. In the proposed double blind study, diabetics with foot ulcers will be randomized to one of five groups (n = 20 per group 1 & 2; n = 3 per group 3; n = 6 per group 4 & 5). Group 1 will receive topical doxycycline and group 2 will receive a vehicle control treatment for 20 weeks. Healing will be measured by assessing wound surface planimetry and volumetric measurements, cytokines, proteases and growth factor activities at baseline, 2, 4, 6, 8,10 weeks and 20 weeks of treatment. Global changes in the relative levels of over 12,000 mRNAs in sequential biopsies from doxycycline-treated and vehicle-treated diabetic foot ulcers using Affymetrix GeneChip(r) analysis will be determined from groups 3, 4 & 5 at baseline, at 10 weeks of treatment, and at 20 weeks of treatment. Data will be analyzed using multivariate methods. Translating advances in the bio molecular and genetic basis of diabetes and diabetic wound healing is needed to improve nursing care and quality of life. [unreadable] [unreadable]